合成和生物评估口服活性的抗Trypanosoma药物
Fatma M Salem1, William R Martin2, Xiaotong Zhao1
1Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
Bioorganic & medicinal chemistry
|May 19, 2024
概括
研究人员优化了anti-trypanosome化合物,以更好地进行口服治疗人类非洲三杆菌病 (HAT). 一种新化合物在小鼠中显示出显著的口服活性,有效地抑制了寄生虫的生长.
科学领域:
- 药用化学 医学化学
- 寄生虫学的寄生虫学
- 药物发现 药物发现 药物发现
背景情况:
- 之前的抗三体氨酸抑制剂在体外显示出对人类非洲三体病 (HAT) 的活性.
- 口服生物可用性对于开发有效的HAT治疗方法至关重要.
研究的目的:
- 优化现有的抗试酶化合物,以提高配体效率,减少体积,改善口服生物可用性.
- 合成和评估具有较低分子量和较少芳香成分的新型类似物.
- 为了建立结构-活性关系 (SAR) 并评估与三体管素的结合亲和力.
主要方法:
- 用组合化学合成了30种新的类似物.
- 在体外测试中使用Trypanosoma brucei brucei细胞和哺乳动物细胞系 (人类脏,小鼠巨细胞) 进行了测试.
- 进行了结构-活性关系 (SAR) 分析和分子对接研究.
主要成果:
- 几种新的类型对试体具有较低的微分子IC50值.
- 化合物表现出选择性,在同等度下抑制寄生虫生长而不损害宿主细胞.
- 在结合能量和抗三体活性之间观察到强烈的相关性.
- 化合物7在小鼠模型中显示出显著的口服疗效,减少了试酶增殖.
结论:
- 可以开发出具有改善物理化学性质的优化抗trypanosome化合物.
- 化合物7代表了作为口服生物可用HAT治疗药物进一步开发的有希望的候选者.
- SAR和对接研究为设计未来的抗寄生虫剂提供了宝贵的见解.
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